Many cancer patients receive radiotherapy (RT) during the course of cancer treatment. RT may be used alone or combined with other treatment modalities. Despite the significant advances in cancer diagnosis, treatment technologies, and research in recent years, the age-adjusted cancer death rate in the United States has not shown a corresponding improvement. Further, quality of life issues have been receiving a growing amount of attention from cancer patients and healthcare providers. Today, the consideration of quality of life is an important factor for many cancer patients and their healthcare providers in choosing cancer management techniques.
Pre-Clinical RT Devices
Improvements in cancer patient survival and quality of life require translational research that assesses tumor control and normal tissue toxicity from a particular treatment concurrently, especially in the case of combined drug and radiation treatment. In addition to the existing cancer fighting drugs, the advances in basic cancer biology, pharmacology, and nanomedicine are expected to produce new promising biomarkers/biosensors, nano-scale agents with cancer-specific imaging contrast, agents loaded with potent cancer killing drugs, radiosensitizers, and radioprotectors. These future cancer-fighting and radiological countermeasure drugs underscore the need to develop new research tools that can facilitate comprehensive and clinically relevant preclinical studies that will be required to evaluate the immediate and long-term effects of these agents on both tumor and normal tissues.
Small animal models have been widely used for basic cancer research. Human tumor xenografts in small animals are commonly used to study drug and radiosensitization efficacy. However, the standard xenograft model of implanting tumor cells at various sites of immunocompromised mice has inherent limitations in that, while easily accessible for irradiation and measurement, tumors created from established cell lines implanted into non-native sites can respond differently than spontaneous tumors arising in their native environment. Recently, orthotopic models have been developed in which cancer types common to humans, such as small cell lung or prostate carcinoma, may be genetically produced in mice. In this case, however, monitoring tumor size by palpation is difficult or impossible for non-superficial sites. Thus, sophisticated, high-resolution imaging tools are required to evaluate response to treatment in most orthotopic tumor models. Furthermore, delivery of radiotherapy for radiosensitization studies using orthotopic models is complicated by the radiation toxicity associated with many sites. Targeted radiotherapy delivery, with confirmation of adequate treatment of the tumor while sparing adjacent normal tissues has been a primary limitation to such studies. Tools are desirable that can provide animal models that may be used to study the interaction between drugs and radiation, as well as provide information for drug development and human clinical application. Appropriate animal models can also be used to study other cancer treatment topics that cannot be adequately addressed by clinical trials. For example, whether new technologies in radiotherapy, especially those with high cost, generate real benefit in terms of local tumor control and quality of life.
One cancer research tool is a small animal irradiator. Current small-animal irradiators, such as Cesium-137 irradiators, have spatial resolution of 1 cm at best and have practically no temporal control for a given radiation dose. Often mouse irradiation intended for the tumor is also unavoidably given to the entire body or a large portion of it. Consequentially severe radiation reactions are prone to develop in the mouse model that can greatly hinder the range of study possible. In human radiotherapy treatment, toxicity is minimized and tumor control is maximized by using state of the art image-based treatment optimization design and high precision delivery technologies. One example is dose optimized conformal radiotherapy, where the radiation dose “wraps around” the tumor and largely avoids critical structures and normal tissues. Because of the lack of imaging devices in most animal model research laboratories, many orthotopic models with internal tumors that are not easily palpable cannot be used for irradiation study. Conformal and fractionated irradiation, as used in human radiotherapy, is also not possible in current small animal irradiation technology. Such technical limitations prevent researchers from fully using the animal models under conditions analogous to those used for human treatment, thereby weakening the clinical relevancy of the research.
Realizing the existing gaps in small animal irradiation technology, one researcher began to develop a micro-RT device using the readily available brachytherapy isotope Ir-192 as the radiation source. The radiation field may be shaped to selected sizes by using a set of physical collimation cones that are suitable for small animal irradiation. Another researcher proposed a combined imaging and irradiation micro-CT-RT small animal research platform where conventional kV x-ray tubes are used for CT imaging and irradiation. There are considerable technical challenges in developing these proposed small animal irradiation and imaging devices to meet the spatial and temporal resolution demands of high quality small animal imaging and conformal irradiation. One challenge is related to the mechanical complexity in the design, fabrication, and control of the miniaturized radiation field collimation system. Assuming that the micro-RT system includes features similar to linear accelerators for human RT, that is, with the high accuracy and automatic collimator motion needed for intensity-modulated treatment, the miniature scale involved in micro-RT irradiation of small animals would be difficult to develop. Another challenge is the temporal resolution required for high quality imaging and image-guided conformal irradiation of live small animals capable of rapid organ motion. Conventional x-ray tubes deliver continuous radiation and thus can lead to motion-blurred images. In addition, the radiation dose from imaging alone may be high. Pulsed irradiation lasting only a fraction of the organ motion cycle is better suited for such imaging and results in less total dose to the animal.
Clinical RT Devices
Medical linear accelerators (LINACs) are the main clinical RT devices in the United States and many other countries. A conventional RT LINAC primarily consists of three major moving components: (1) a treatment table in a horizontal position to hold the patient under the radiation beam; (2) a gantry system that can be rotated in a vertical plane and from which a radiation beam is aimed at the patient on the treatment table; and (3) a physical beam collimator system (at the end of the gantry) that mechanically defines the shape and location of the radiation field. Each of the three moving components can rotate about its own rotation axis and all three axes meet at one point in space, which is referred as the LINAC isocenter. Often, a patient is setup for treatment so that the isocenter is inside the treatment target tumor. Using this conventional LINAC system a typical RT treatment consists of 3-6 radiation fields. Each field enters the patient from a different angle to form a conformal radiation distribution around the treatment target volume. The radiation collimation devices of a LINAC may include movable jaws, lead alloy custom blocks, and automated multi-leaf collimator (MLC) systems. A MLC system can be consist of more than 100 pairs of individual collimator leaves, each leaf is controlled by a motor that drives the leaf motion and an encoder that reads the position of the MLC leaf. For intensity-modulated radiotherapy (IMRT), a treatment that is designed to maximize both the tumor control and normal tissue sparing, the MLC leaves are programmed to move with predefined pattern and speed during or between radiation deliveries. Therefore, modern conventional clinical LINAC is very complicated mechanically and electronically, and the there are mechanical constraints on MLC motion (configuration and speed) so that some radiation field configurations and intensity patterns are not physically possible.
Recently, a new type of clinical LINAC called Tomotherapy has received wide acceptance. A Tomotherapy unit resembles more of a CT scanner than the conventional clinical LINAC. Within a donut structure, the RT x-ray accelerating waveguide physically rotates around the patient, similar to the x-ray tube rotating inside a CT scanner. The high energy RT x-rays are used radiation treatment and CT imaging. Tomotherapy uses the same mechanical means approach as conventional clinical LINAC for radiation field shaping and intensity modulation.
X-ray imaging and CT imaging are increasingly used in RT cancer treatment to accurately align patient with radiation fields in the fractionated treatment course. This new technology is referred as Image-Guided Radiotherapy (IGRT). IGRT has the potential to significantly increase the quality of highly conformal and intensity-modulated treatment by accurately aligning the patient under radiation beams in daily treatment. Currently, RT treatment imaging can be done using several methods including a separate CT scanner placed inside the treatment room, a kV x-ray imaging system attached to the treatment accelerator, and an imaging system using directly the treatment beam, as in the case of Tomotherapy. These IGRT methods all rely on a mechanically rotating x-ray source for imaging. Both the conventional clinical LINAC and Tomotherapy use mechanical motion of MLC leaves to define radiation field shape and its intensity distribution.
In all existing RT technologies, x-rays are controlled by mechanical means—the direction from which the x-ray radiation field arrived (gantry), the radiation field shape (MLC), and the radiation intensity distribution within the field (MLC). This dependence on mechanical means hinders the advancement of the RT technologies to meet the increasing demand to deliver RT treatments with higher spatial and temporal resolution for better treatment outcome. The increasingly complex mechanical components and thus their electronic control systems can also significantly raise the cost of cancer treatment (device purchase cost and the ongoing maintenance cost include technical staff) and at the same time drop reliability of the RT machine.
Accordingly, there exists a need for technology that forms the spatial and temporal feature of RT x-ray radiation field electronically without mechanical motion. In pre-clinical RT application, it is desirable to have technology operable to provide high-resolution conformal irradiation to small animal models for making animal model studies more clinically relevant. In the clinical application, it is desirable to have technology for leading to a new generation of clinical RT devices that can better meet the increasingly high demand on radiation manipulation and cancer treatment cost containment.